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Cited by 153Angiogenesis and VEGF in CancerIon Channels and ReceptorsLymphatic System and Diseases

Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy

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Adapala, R K, Thoppil, R J, Ghosh, K, Cappelli, H C, Dudley, A C, Paruchuri, S, Keshamouni, V, Klagsbrun, M +4 more·2016·Oncogene
DOI 10.1038/onc.2015.83PMC PMC4948740
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Abstract

Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.

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  • HUVECs may not entirely recapitulate all known roles for TRPV4 in tumor vasculature.

    “HUVECs may not entirely recapitulate all known roles for TRPV4 in tumor vasculature. 24,28,35,51,53,66”

    From Rapid Assessment of Nanoparticle Extravasation in a Microfluidic Tumor Model (2019) · cites this paper as [66]

    The Results section on tumor endothelial cells reports lower TRPV4 expression in tumor-derived cells than in normal endothelial cells, and the mouse tumor results link TRPV4 loss to abnormal tumor vessels (page unavailable in our copy). These findings support the concern that normal endothelial cells may not capture every tumor-vascular role of TRPV4, but the paper does not study HUVECs or assess their suitability as a model. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Authors
Adapala, R. K., Thoppil, R. J., Ghosh, K., Cappelli, H. C., Dudley, A. C., Paruchuri, S., Keshamouni, V, Klagsbrun, M., Meszaros, J. G., Chilian, W. M., Ingber, D. E., & Thodeti, C. K.
Affiliations
  • Kent State University (US)
  • University of California, Riverside (US)
  • University of North Carolina at Chapel Hill (US)
  • University of Akron (US)
  • University of Michigan (US)
  • Boston Children's Hospital (US)
Corresponding author
Thodeti, C K
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2015-04-13
Volume
35
Issue
3
Pages
314-322
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2015.83
PMC
PMC4948740
OpenAlex
W2071494920
Cited by
153
References
4
Citations by year
2026: 5 · 2025: 10 · 2024: 15 · 2023: 10 · 2022: 21 · 2021: 20 · 2020: 21 · 2019: 19 · 2018: 18 · 2017: 5 · 2016: 8 · 2015: 1
FWCI
4.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
  • UNC Libraries
Funders
  • Northeast Ohio Medical University
  • National Institutes of Health (1r15ca202847-01, CA-45548)
  • National Heart, Lung, and Blood Institute (R15HL106442, R01HL032788, R01HL115114, R01HL119705, R01HL083366)
  • National Cancer Institute (CA55833, P01CA045548, CA-45548, R15CA202847, R01CA055833, R01CA177875, P30CA016086)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Keywords
TRPV4, mechanosensitive ion channels, tumor angiogenesis, tumor vasculature normalization, tumor endothelial cells, mechanosensitivity, extracellular matrix stiffness, pericyte coverage, GSK1016790A, cisplatin combination therapy, anti-angiogenic therapy, vascular maturation
MeSH terms
Animals, Cisplatin, Endothelium, Vascular, Humans, Leucine, Neovascularization, Pathologic, Sulfonamides, Gene Expression Regulation, Neoplastic, Carcinoma, Lewis Lung, Calcium Signaling, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Cell Proliferation, TRPV Cation Channels, Mice

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